Andrew Morrison and colleagues utilized the lymph node expertise from the Reina Mebius lab and the organotypic modeling skills of the Sue Gibbs Skinlab. Together, they successfully developed and characterized the beginning of an innovative organotypic 3D human lymph node (LN) model, specifically incorporating fibroblast reticular cells (FRCs). This model enabled a comprehensive exploration of the impact of FRCs on Dendritic Cells (DCs). The findings from this work are now available in the Journal for Tissue Engineering and Regenerative Medicine (TERM).
To break it down, human lymph nodes are essential for our immune system. They are where certain immune cells, such as DCs, activate and train other immune cells (B and T cells) to mount a specific immune response, like producing antibodies against invaders. Therefore, they maintain our health and combat diseases. Despite the pivotal role of FRCs in LN functioning, particularly in organizing the LN cellular architecture and facilitating antigen presentation, their inclusion and recognition of importance in organotypic in vitro LN models have been limited.
To address this gap, Andrew Morrison and colleagues combined the LN expertise of the Reina Mebius lab with the technical skills in 3D organ modeling from the Sue Gibbs Skinlab. The collaborative effort aimed to develop an in vitro human LN model centered around the inclusion of primary FRCs and DCs. They used a special gel that mimics the natural environment of human LNs to build a 3D model, allowing these cells to interact as they would in our body.
Crucial Insights into Dendritic Cell Survival, Proliferation, and Differentiation
Having established an in vitro human LN model centered around FRCs, the findings underscore the pivotal role of FRCs for DC function. FRCs were found to secrete survival and proliferative signals for DCs in the 3D LN model, as notably the absence of FRCs resulted in a lack of viable DCs, emphasizing the dependence of DCs on FRCs in 3D. Furthermore, the study revealed that FRCs possessed the capability to guide the differentiation of DCs in 3D after cytokine stimuli towards a phenotype resembling LN-resident DCs, which could be detected in the native human LN. Intriguingly, these DCs retained their functional status, as evidenced by their ability to induce T cell proliferation in a mixed leukocyte reaction.
Andrew Morrison explains: “Our main message is that if you want to study the behaviour of immune cells in a 3D model, a stromal cell component, in this case FRCs, are not only physiologically relevant, but vital! Our study also revealed that the FRCs in our model closely resemble the ones supporting DCs in human LNs. This means our model accurately mimics the natural environment, giving us the right cell types to study how DCs act in a LN-like setting in the lab. We are currently working on improving the model by adding more immune cell types to make it even more realistic. This advancement makes the model a valuable tool for testing immunotherapies and gaining insights into diseases related to our LNs. It helps in understanding how immune cells behave differently in various organs, paving the way for more precise therapeutic approaches targeting the immune system.”
The Next Generation of 3D Human Lymph Nodes with Enhanced Realism and Integration into (Multi)-Organ-on-Chips
“Our research marks the initial step towards the next generation of 3D human LNs, with the incorporation of additional immune cells for enhanced authenticity”, Andrew Morrison states. The ultimate goal for the researchers is to advance these 3D models for integration into a type of microphysiological system called (multi)-organ-on-chips. This innovative approach involves bringing the 3D LN model into a microfluidic device (chip) that will allow parameters such as flow and sheer stress that cannot be administered in static in vitro models. These microfluidic devices can be designed in such a way to facilitate the culture of multiple organ models on the one chip. This gives the ability to recreate and try study the migration of immune cells from one tissue model, such as skin or gut, into the LN model in vitro, emulating a more systemic-like immune response that happens in the human body.
For more information contact Andrew Morrison or read the scientific publication below:
DOI: 10.1007/s13770-023-00609-x
Open access: https://rdcu.be/dt4pU
Researchers involved:
Andrew I. Morrison1,2, PhD Student
Aleksandra M. Mikula1,2, Research Technician
Sander W. Spiekstra1,2, Senior Research Technician
Michael de Kok1,2, Embedded (Supporting) Bioinformatician
Alsya J. Affandi1,2,3, Senior Post-Doc
Henk P. Roest4, Senior Scientist
Luc J.W. van der Laan4, Professor, Head of Laboratory (LETIS)
Charlotte M. de Winde1,2,3, Senior Post-Doc
Jasper J. Koning1,2, Senior Post-Doc
Susan Gibbs1,2,5, Professor in Skin and Mucosa Regenerative Medicine
Reina E. Mebius1,2, Professor in Molecular Cell Biologyand Immunology
1Amsterdam UMC location Vrije Universiteit Amsterdam, Molecular Cell Biology & Immunology, De Boelelaan 1117, Amsterdam, The Netherlands.
2Amsterdam institute for Infection and Immunity, Amsterdam, The Netherlands.
3Cancer Center Amsterdam, Amsterdam, The Netherlands
4Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Dr. Molewaterplein 40, 3015GD, Rotterdam, The Netherlands.
5Department Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands.
Funding:
This project is supported by the European Union's Horizon 2020 research and innovation programme, grant agreement No 847551 ARCAID - Amsterdam Rheumatology Centre for Autoimmune Diseases.
Text: Esmée Vesseur and Andrew Morrison
Picture: the Reina Mebius Lab, Andrew Morrison is pictured on the left in his blue polo shirt.